Kidney failure is a critical health problem in the United States and it reflects the consequences of failed nephron repair and progressive fibrosis. Two promising strategies to treat kidney failure include regeneration of functional nephrons in vivo, and engineering of transplantable nephrons in vitro. We have identified two critical adult kidney progenitor populations with strong potential to play important roles in each strategy. Within the tubule, we have previously shown that dedifferentiated proximal tubule cells are responsible for repairing proximal tubule by proliferative expansion. We have now generated a novel approach to easily isolate a pure population of these dedifferentiated epithelial progenitors, and we will characterize, culture and define the functional properties of these critical cells. In addition, we have recently identified a kidney resident mesenchymal stem cell population defined by expression of Gli1 that represents the major myofibroblast precursor population in fibrotic disease. These cells have vascular stabilizing properties and are capable of differentiating into both pericytes and vascular smooth muscle cells. We will further characterize the function of these cells both in vitro and in vivo, and coculture them with endothelial cells and epithelial cels to model the kidney tubulointerstitium in vitro. Together, the proposed experiments will not only define novel regenerative strategies for kidney failure, but will also validate two critical adult progenitor cell populations that will be useful for a variety of regenerative approaches to treat kidney failure.